Over half of the U.S. population consumes alcohol and intoxication has been implicated in nearly all forms of traumatic injury, including burns. Alcohol exposure prior to burn escalates morbidity and mortality, though the mechanism of this interaction is unknown. As a central organ sensitive to cytokine signaling and alcohol metabolism, the liver is positioned to be enmeshed in this injurious response. The studies proposed herein intend to elucidate the role of the liver in the common setting of burn injury preceded by ethanol exposure and determine the cellular mechanisms involved so that targeted approaches to therapeutic intervention can be identified. Of the cytokines elevated when alcohol exposure precedes a burn, IL-6 has been correlated with increased mortality risk in trauma patients. Within the liver, Kupffer cells are a source of IL-6 production and function to orchestrate hepatic responses to products in the blood, including ethanol and endotoxin. Ethanol sensitizes Kupffer cells to gut-derived endotoxin through a variety of mechanisms including activation of the Toll-like receptor 4 (TLR4) signaling proteins such as mitogen activated protein kinase (MAPK). Additionally, both ethanol and burn injury have independently been shown to increase intestinal permeability and gut- derived endotoxin which signals through TLR4 on Kupffer cells and causes their activation and subsequent IL- 6 production. From these pieces of evidence, we hypothesize that alcohol intoxication exacerbates the hepatic response to burn injury through a feed forward loop involving Kupffer cell sensitization to gut- derived LPS, increased intestinal permeability and hepatic IL-6 production. To test this hypothesis, we will use our well-established mouse model of alcohol exposure and burn injury to (Aim1) determine the effects of episodic binge ethanol on the post burn hepatic response. This will be investigated through multiple measures of hepatocellular damage, indices of liver function, and pro-inflammatory cytokine production. We will then (Aim2) determine if depletion of Kupffer cells or restoring gut barrier function attenuates hepatic damage and IL-6 production after ethanol intoxication and burn injury. This will be accomplished by administering clodronate liposomes in vivo to deplete Kupffer cells and administering membrane-permeant inhibitor of kinase (PIK) in vivo to reduce intestinal permeability. Finally, in our third aim we will (Aim3) identify the speciic MAPK isoforms in Kupffer cells responsible for TLR4-induced production of IL-6 after episodic binge ethanol and burn injury. Taken together, these studies will expand on our knowledge of how ethanol deranges the hepatic response to burn, and by identifying the mechanisms of this response, may reveal therapeutic strategies to alleviate the excessive morbidity and mortality in this patient population.